PROJECT SUMMARY Autism spectrum disorders (ASDs) are a group of neuropsychiatric conditions with a great deal of phenotypic variability. Emerging genetic analyses have unequivocally demonstrated that a variety of genetic factors create ASD risk, including common polygenic variation, de novo variation, rare inherited variation, and copy number variation. To understand how these diverse genetic factors influence risk for ASDs, we will evaluate the full spectrum of phenotypes with which they are associated, both in ASD cases and in the general population. In so doing, we will identify types of ASD-associated genetic variation that appear similar in terms of phenotypic impact and, critically, highlight types that diverge. To characterize the relationship between ASD genetic risk and phenotypic heterogeneity in ASD cases, we will leverage a new resource of over 13,000 ASD cases from the Danish national psychiatric registry. We will examine how common polygenic variation and rare protein truncating variation (point mutations and CNVs) relate to phenotypic differences in ASD cases. These analyses will identify subgroups of cases that share similar genetic etiology and phenotypic presentation, allowing us to stratify ASD populations for research and eventual treatment development. Using data from two cohort studies, we will also characterize the association between genetic risk for ASDs and behavioral and cognitive variation in the general population. We will conduct a phenome-wide association study of the relationship between common polygenic risk for ASDs and behavioral, cognitive, and medical variation in the Philadelphia Neurodevelopmental Cohort (PNC; n=7500). In the Twins Early Development Study, we will examine the general population relationship between rate of rare, protein truncating variation and each of: intelligence, autism-like traits, psychosis-like traits, and traits of attention deficit disorder. Significant genetic associations with general population phenotypes will facilitate interpretation of ASD risk variants, and inform our understanding of clinical thresholds. The projects described in this proposal will significantly improve understanding of ASDs heterogeneity and genetic influences.